We studied the timing and duration of adjuvant chemotherapy for operable breast cancer with axillary-node involvement in a randomized trial including 1229 patients divided into three treatment groups. One group received a single perioperative course of adjuvant combination chemotherapy beginning within 36 hours of mastectomy; a second received six cycles of conventionally timed adjuvant chemotherapy starting 25 to 32 days after operation; and a third received both the perioperative cycle and the conventionally timed regimen. The chemotherapy consisted of cyclophosphamide, methotrexate, and fluorouracil. Tamoxifen was added to the conventionally timed regimen in postmenopausal women. At a median follow-up of 42 months, the estimated four-year disease-free survival was 40 percent for the single perioperative cycle, 62 percent for the longer, conventionally timed regimen, and 60 percent for the combined program (P less than 0.0001). Overall survival differences also favored the longer treatments (P = 0.011). We conclude that a single perioperative cycle of adjuvant combination chemotherapy is less effective than prolonged therapy in patients with operable breast cancer and involved axillary nodes. Furthermore, starting the prolonged therapy perioperatively is no more effective than starting treatment four weeks after mastectomy.

We randomly assigned 46 patients (mean age, 11.7 years; range, 4.5 to 32.8) with newly diagnosed insulin-dependent diabetes mellitus within two weeks of beginning insulin to receive either corticosteroids for 10 weeks plus daily azathioprine for one year or no immunosuppressive therapy. Half the 20 immunosuppressed patients completing the one-year trial had satisfactory metabolic outcomes (hemoglobin A1c less than 6.8 percent; stimulated peak C peptide greater than 0.5 nmol per liter; insulin dose less than 0.4 U per kilogram of body weight per day) as compared with only 15 percent of the controls. Three of 20 immunosuppressed patients, but no controls, were insulin independent at one year. Two of these continue to receive azathioprine without insulin after more than 27 months of follow-up. The response to immunosuppression correlated with older age, better initial metabolic status, and lymphopenia (less than 1800 lymphocytes per cubic millimeter) resulting from immunosuppression. The side effects of azathioprine included vomiting in one patient and mild hair loss in several others. Prednisone use resulted in a transient cushingoid appearance, weight gain, and hyperglycemia. The growth rate remained normal in all patients. We conclude that early immunosuppression with short-term use of corticosteroids plus daily azathioprine can improve metabolic control in some patients with insulin-dependent diabetes mellitus, but results from this unblinded study are preliminary and require further confirmation and long-term follow-up.

Encephalitis caused by Japanese encephalitis virus occurs in annual epidemics throughout Asia, making it the principal cause of epidemic viral encephalitis in the world. No currently available vaccine has demonstrated efficacy in preventing this disease in a controlled trial. We performed a placebo-controlled, blinded, randomized trial in a northern Thai province, with two doses of monovalent (Nakayama strain) or bivalent (Nakayama plus Beijing strains) inactivated, purified Japanese encephalitis vaccine made from whole virus derived from mouse brain. We examined the effect of these vaccines on the incidence and severity of Japanese encephalitis and dengue hemorrhagic fever, a disease caused by a closely related flavivirus. Between November 1984 and March 1985, 65,224 children received two doses of monovalent Japanese encephalitis vaccine (n = 21,628), bivalent Japanese encephalitis vaccine (n = 22,080), or tetanus toxoid placebo (n = 21,516), with only minor side effects. The cumulative attack rate for encephalitis due to Japanese encephalitis virus was 51 per 100,000 in the placebo group and 5 per 100,000 in each vaccine group. The efficacy in both vaccine groups combined was 91 percent (95 percent confidence interval, 70 to 97 percent). Attack rates for dengue hemorrhagic fever declined, but not significantly. The severity of cases of dengue was also reduced. We conclude that two doses of inactivated Japanese encephalitis vaccine, either monovalent or bivalent, protect against encephalitis due to Japanese encephalitis virus and may have a limited beneficial effect on the severity of dengue hemorrhagic fever.

There is reason to believe that diabetic neuropathy may be related to the accumulation of sorbitol in nerve tissue through an aldose reductase pathway from glucose. Short-term treatment with aldose reductase inhibitors improves nerve conduction in subjects with diabetes, but the effects of long-term treatment on the neuropathologic changes of diabetic neuropathy are unknown. To determine whether more prolonged aldose reductase inhibition reverses the underlying lesions that accompany symptomatic diabetic peripheral polyneuropathy, we performed a randomized, placebo-controlled, double-blind trial of the investigational aldose reductase inhibitor sorbinil (250 mg per day). Sural-nerve biopsy specimens obtained at base line and after one year from 16 diabetic patients with neuropathy were analyzed morphometrically in detail and compared with selected electrophysiologic and clinical indexes. In contrast to patients who received placebo, the 10 sorbinil-treated patients had a decrease of 41.8 +/- 8.0 percent in nerve sorbitol content (P less than 0.01) and a 3.8-fold increase in the percentage of regenerating myelinated nerve fibers (P less than 0.001), reflected by a 33 percent increase in the number of myelinated fibers per unit of cross-sectional area of nerve (P = 0.04). They also had quantitative improvement in terms of the degree of paranodal demyelination, segmental demyelination, and myelin wrinkling. The increase in the number of fibers was accompanied by electrophysiologic and clinical evidence of improved nerve function. We conclude that sorbinil, as a metabolic intervention targeted against a specific biochemical consequence of hyperglycemia, can improve the neuropathologic lesions of diabetic neuropathy.

Recurrent respiratory papillomatosis is a relentless disease of viral origin in which squamous papillomas frequently obstruct the respiratory tract of children and young adults. No therapy has been proved to be curative for this process. Recent reports have suggested that interferon may cure or dramatically control airway papillomatosis. We evaluated the efficacy of human leukocyte interferon in the treatment of respiratory papillomatosis. One hundred twenty-three patients were randomly assigned to receive treatment with either surgery plus interferon or surgery alone. Interferon (2 X 10(6) IU per square meter of body-surface area) was given daily for one week, then three times per week for one year; treatment was followed by a year of observation, without the drug. Both study groups underwent serial endoscopy to remove papillomas and to document the efficacy of treatment during the two years of study. During the first six months, the growth rate of papillomas in the interferon group was significantly lower than in the control group (P = 0.0007). This difference diminished during the second six months and was no longer statistically significant (P = 0.68). Our data do not show that interferon is either curative or of substantial value as an adjunctive agent in the long-term management of recurrent respiratory papillomatosis. The initial benefit of interferon is not sustained.

We studied the effect of diltiazem on mortality and reinfarction in 2466 patients with previous infarction from 38 hospitals in the United States and Canada. The patients were randomly assigned to receive diltiazem (240 mg per day, n = 1234) or placebo (n = 1232) and followed for 12 to 52 months (mean, 25). Total mortality rates were nearly identical among the two treatment groups (167 and 166, respectively), as were cumulative mortality rates. There were 11 percent fewer first recurrent cardiac events (death from cardiac causes or nonfatal reinfarction) in the diltiazem group than in the placebo group (202 vs. 226; Cox hazard ratio, 0.90; 95 percent confidence limits, 0.74 and 1.08). A significant (P = 0.0042) bidirectional interaction between diltiazem and pulmonary congestion was observed on x-ray examination. In 1909 patients without pulmonary congestion, diltiazem was associated with a reduced number of cardiac events (hazard ratio, 0.77; 95 percent confidence limits, 0.61 and 0.98); in 490 patients with pulmonary congestion, diltiazem was associated with an increased number of cardiac events (hazard ratio, 1.41; 95 percent confidence limits, 1.01 and 1.96). A similar pattern was observed with respect to the ejection fraction, which was dichotomized at 0.40. Thus, diltiazem exerted no overall effect on mortality or cardiac events in this population of patients with previous infarction. This neutral effect reflected a diltiazem-related reduction in cardiac events in the majority of patients without left ventricular dysfunction and an increase in such events in the minority of patients with left ventricular dysfunction.

We conducted a randomized study of 100 patients to examine the efficacy and risks of two methods of urinary-bladder management after total joint-replacement surgery. Patients who had hip or knee replacement were randomly assigned either to Group I, in which indwelling catheters were placed during the operation and removed the next morning, or Group II, in which urinary retention was treated by intermittent catheterization as needed. After the removal of the indwelling catheter, the patients in Group I had a lower incidence of urinary retention than those in Group II (27 vs. 52 percent; P less than 0.01). Bladder distention (volume above 700 ml) was more common in Group II (45 percent as compared with 7 percent in Group I; P less than 0.01) and was associated with an increased need for subsequent long-term catheterization. There was no significant difference between the groups in the rates of urinary tract infection (11 vs. 15 percent). We could not identify patients at high risk for retention or infection on the basis of preoperative urinary symptoms, previous urinary tract surgery, previous urinary tract infection or urinary retention, high-risk medical conditions, sex, type of anesthesia, or age (in the absence of prophylactic treatment). We conclude that the short-term use of an indwelling catheter after extended surgery, such as joint replacement, reduces the incidence of urinary retention and bladder overdistention, without increasing the rate of urinary tract infection.

We studied survival rates among 767 men with good left ventricular function who participated in the European Coronary Surgery Study, 10 to 12 years after they were randomly assigned to either early coronary bypass surgery or medical therapy. At the projected five-year follow-up interval, we observed a significantly higher survival rate (+/- 95 percent confidence interval) in the group that was assigned to surgical treatment than in the group assigned to medical treatment (92.4 +/- 2.7 vs. 83.1 +/- 3.9 percent; P = 0.0001). During the subsequent seven years, the percentage of patients who survived decreased more rapidly in the surgically treated than in the medically treated group (70.6 +/- 5.8 vs. 66.7 +/- 5.3 percent at 12 years). Thus, the improvement in the survival rate among patients with stable angina who were treated surgically appears to have been attenuated after five years. However, the gradually diminishing difference between the two survival curves still favored surgical treatment after 12 years (P = 0.04), despite the fact that 136 patients in the medically treated group had coronary bypass surgery and 23 in the "surgically treated" group did not. The benefit of surgical treatment tended to be greater, but not significantly so, as assessed by interaction analysis in the subgroups of patients who were older or who had signs of ischemia or previous infarction on the resting electrocardiogram, a markedly ischemic response to exercise testing, peripheral arterial disease, an absence of hypertension, and proximal obstruction in the left anterior descending artery. The reasons for the loss of a beneficial effect of surgery after five years are unknown and merit further study.

We conducted a double-blind, placebo-controlled trial to determine whether ventricular dilatation continues during the late convalescent phase after myocardial infarction and whether therapy with captopril alters this process. Fifty-nine patients with a first anterior myocardial infarction and a radionuclide ejection fraction of 45 percent or less underwent cardiac catheterization 11 to 31 days after infarction, when they were not in overt congestive heart failure. They were randomly assigned to placebo or captopril and were followed for one year. A repeat catheterization was performed to evaluate interval changes in hemodynamic function and left ventricular volume. Thirty-eight male patients were evaluated with maximal-exercise treadmill tests every three months. No differences were detected at base line in clinical, hemodynamic, or quantitative ventriculographic variables. During one year of follow-up, the end-diastolic volume of the left ventricle increased by a mean [+/- SEM] of 21 +/- 8 ml (P less than 0.02) in the placebo group, but by only 10 +/- 6 ml (P not significant) in the captopril group. The left ventricular filling pressure remained elevated with placebo but decreased (P less than 0.01) with captopril. In a subset of 36 patients who were at high risk for ventricular enlargement because they had persistent occlusion of the left anterior descending coronary artery, captopril prevented further ventricular dilatation (P less than 0.05). Patients given captopril also had increased exercise capacity (P less than 0.05). This preliminary study indicates that after anterior myocardial infarction, ventricular enlargement is progressive and that captopril may attenuate this process, reduce filling pressures, and improve exercise tolerance.

The value of sclerotherapy as prophylaxis against the first episode of variceal hemorrhage has not been established. Therefore, we randomly assigned 133 patients with cirrhosis of the liver (of alcoholic origin in 66 percent), esophageal varices, and no previous intestinal bleeding to either prophylactic sclerotherapy (n = 68) or no prophylaxis (n = 65). The groups were comparable in hepatic function, endoscopic findings, and the pathogenesis of cirrhosis. All patients who subsequently had a first episode of variceal hemorrhage received sclerotherapy whenever possible. During a median follow-up of 22 months, variceal hemorrhage occurred in 28 percent of the patients receiving sclerotherapy and 37 percent of the controls (P = 0.3). Thirty-five percent of the sclerotherapy group and 46 percent of the control group died. The survival curves (Kaplan-Meier) of both groups were similar (P = 0.2). However, among patients with alcoholic and moderately decompensated cirrhosis (Child-Pugh group B), survival was significantly higher in those receiving sclerotherapy, although the risk of bleeding was only marginally reduced by this procedure. We conclude that prophylactic sclerotherapy does not significantly reduce the risk of bleeding from esophageal varices, but that a subgroup of patients with esophageal varices and moderately decompensated alcoholic cirrhosis may benefit from prophylactic sclerotherapy because of factors not solely attributable to prevention of an initial episode of variceal bleeding.

In a randomized clinical trial, we evaluated the efficacy of an oral immunoglobulin preparation (73 percent IgA and 26 percent IgG) in reducing the incidence of necrotizing enterocolitis in infants of low birth weight for whom breast milk from their mothers was not available. A total of 434 infants weighing between 800 and 2000 g were eligible for entry in the study. Of these, 255 were withdrawn - 234 during the first week of the study because breast milk from their mothers became available (123 in the treatment group and 111 in the control group), and 21 because of violations of protocol or because breast milk became available after the first week. The duration of follow-up was 28 days. Among the infants for whom breast milk did not become available during the study, there were no cases of necrotizing enterocolitis among the 88 receiving oral IgA-IgG, as compared with six cases among the 91 control infants (P = 0.0143). Of the infants withdrawn from the study, two assigned to the control group had necrotizing enterocolitis. We conclude that the oral administration of IgA-IgG may prevent the development of necrotizing enterocolitis in low-birth-weight infants.

There is preliminary evidence that colchicine, an inhibitor of collagen synthesis, may be beneficial in the treatment of cirrhosis of the liver. To evaluate the use of colchicine (1 mg per day, five days per week) in the treatment of hepatic cirrhosis, we performed a randomized, double-blind, placebo-controlled trial in which 100 patients were followed for up to 14 years. Forty-five patients had alcoholic cirrhosis, 41 had posthepatitic cirrhosis, and the remaining 14 had cirrhosis with various other causes. Histologic studies were available for 92 percent of patients. Seventy-three patients were in Child-Turcotte class A, 26 were in class B, and one was in class C. Fifty-four patients received colchicine, and 46 received placebo. The overall survival in the colchicine group was markedly better than in the placebo group (median survival, 11 and 3.5 years, respectively; P less than 0.001). The cumulative 5-year survival rates were 75 percent in the colchicine group and 34 percent in the placebo group; the corresponding 10-year survival rates were 56 percent and 20 percent. Among the 30 patients treated with colchicine who underwent repeated liver biopsies, histologic improvement was seen in 9; the liver appeared normal in 2, and 7 had minimal portal fibrosis. No histologic improvement was observed in the 14 members of the placebo group who had two or more biopsies. Few side effects were observed in either group.

To examine the role of antiplatelet therapy in the prevention of arterial restenosis after percutaneous transluminal coronary angioplasty (PTCA), we conducted a randomized, double-blind, placebo-controlled study in 376 patients. The active treatment consisted of an oral aspirin-dipyridamole combination (330 mg-75 mg) given three times daily, beginning 24 hours before PTCA. Eight hours before PTCA, the oral dipyridamole was replaced with intravenous dipyridamole at a dosage of 10 mg per hour for 24 hours, and oral aspirin was continued. Sixteen hours after PTCA, the initial combination was reinstituted. Treatment was continued in patients with a successfully dilated vessel until follow-up angiography four to seven months after PTCA--or earlier, if symptoms dictated. Of 249 patients who underwent follow-up angiography, 37.7 percent of patients receiving the active drug had restenosis in at least one segment, as compared with 38.6 percent of patients taking placebo (P not significant). The number of stenotic segments was virtually the same in the two groups. Among the 376 randomized patients, there were 16 periprocedural Q-wave myocardial infarctions--13 in the placebo group and 3 in the active-drug group (6.9 percent vs. 1.6 percent, P = 0.0113). Although the use of this antiplatelet regimen before and after PTCA did not reduce the six-month rate of restenosis after successful coronary angioplasty, it markedly reduced the incidence of transmural myocardial infarction during or soon after PTCA. Thus, the short-term use of antiplatelet agents in relation to PTCA can be recommended.

To confirm reports that skin cancer can be prevented with retinoids, we conducted a three-year controlled prospective study of oral isotretinoin (also called 13-cis retinoic acid) in five patients with xeroderma pigmentosum who had a history of multiple cutaneous basal-cell or squamous-cell carcinomas. Patients were treated with isotretinoin at a dosage of 2 mg per kilogram of body weight per day for two years and then followed for an additional year, without the drug. Before, during, and after treatment, biopsies of all suspicious lesions were performed, and skin cancers were surgically removed. The patients had a total of 121 tumors (mean, 24; range, 8 to 43) in the two-year interval before treatment. During two years of treatment with isotretinoin, there were 25 tumors (mean, 5; range, 3 to 9), with an average reduction in skin cancers of 63 percent (P = 0.019). After the drug was discontinued, the tumor frequency increased a mean of 8.5-fold (range, 2- to 19-fold) over the frequency during treatment (P = 0.007). Although all patients experienced mucocutaneous toxic effects, and triglyceride, liver-function, or skeletal abnormalities developed in some, high-dose oral isotretinoin was effective in the chemoprophylaxis of skin cancers in patients with xeroderma pigmentosum.